Field of the Invention
The present invention relates generally to the fields of medicine and pharmaceuticals. More particularly, it concerns immunogenic compositions, methods of making such compositions, and methods for preventing, treating, ameliorating the symptoms of, and managing a microbial infection, and particularly respiratory infections such as influenza or pneumococcal infection. Disclosed are target peptide antigen sequences or other epitopes that are conserved across related microbes, and even unrelated microbes, as well as immunogenic compositions and methods for their use in the formulation and administration of diagnostic and therapeutic agents for treating and/or preventing disease.
Description of Related Art
Microbial and viral pathogens are a primary source of infectious disease in animals. Pathogens and their hosts constantly adapt to one another in an endless competition for survival and propagation. Certain pathogens have become enormously successful at infecting mammalian hosts and surviving exposure to the host immune response, even over periods of years or decades. One example of an extremely successful mammalian pathogen is the influenzavirus.
Influenzaviruses
Influenzaviruses are etiologic agents for a contagious respiratory illness (commonly referred to, and referred to herein, as “flu” or “the Flu”) that primarily affects humans and other vertebrates. Influenzavirus infection can cause mild to severe illness, and can even lead to death. Every year in the United States, on average, 5% to 20% of the population contract the Flu; more than 200,000 people are hospitalized from complications of the infection; and about 36,000 people die from exposure to the pathogen.
Influenzavirus spreads from host to host through coughing or sneezing, with airborne droplets nuclei as the primary vectors of the disease. In humans, the virus usually spreads directly from person to person, although subjects can sometimes become infected by indirect contact of surfaces harboring the virus, and then touching their mouth or nose. Most healthy adults may be able to infect others beginning as much as a day before primary symptoms of the disease develop, and remain contagious for up to 5 days after becoming infected. Uncomplicated influenza illness is often characterized by an abrupt onset of constitutional and respiratory symptoms, including fever, myalgia, headache, malaise, nonproductive cough, sore throat, rhinitis, or a combination of one or more of these symptoms.
Influenza
Currently, the spread of pathogenic influenzavirus is controlled in animal populations by vaccination and/or treatment with one or more anti-viral compounds. Inactivated influenza vaccines are now in worldwide use, especially in high-risk groups such as infants, the elderly, those without adequate health care and immunocompromised individuals. The vaccine viruses are grown in fertile hen's eggs, inactivated by chemical means and purified. The vaccines are usually trivalent, containing representative influenza A viruses (H1N1 and H3N2) and influenza B strains. The vaccine strains need to be regularly updated in order to maintain efficacy; this effort is coordinated by the World Health Organization (WHO). During inter-pandemic periods, it usually takes a minimum of eight months before an updated influenza vaccine is ready for market. Historically, however, viral pandemics are spread to most continents within four to six months, and future viral pandemics are likely to spread even faster due to increased international travel. It is therefore inevitable that an effective vaccine made by conventional means will be unavailable or in very short supply during the first wave of any future widespread outbreak or pandemic.
Numerous vaccines capable of producing a protective immune response specific for such different and influenza viruses/virus strains have been produced in the last half century. These include whole virus vaccines, split virus vaccines, surface antigen vaccines and live attenuated virus vaccines. However, while appropriate formulations of any of these vaccine types are capable of producing a systemic immune response, live attenuated virus vaccines have the advantage of also being able to stimulate local mucosal immunity in the respiratory tract.
Because of the continual emergence (or re-emergence) of different influenza strains, new influenza vaccines are continually desired. Such vaccines typically are created using antigenic moieties of the newly emergent virus strains, thus, polypeptides and polynucleotides of novel, newly emergent, or newly re-emergent virus strains (especially sequences of antigenic genes) are highly desirable.
Influenza Epidemiology
Because of the rapid mutation rate among Influenzaviruses, it is commonly believed that pandemic Flu could appear at any time. The severity of the next Influenza pandemic cannot be predicted, but modeling studies suggest that the impact of a pandemic on the United States, and the world as a whole, could be substantial. In the absence of any control measures (vaccination or drugs), it has been estimated that in the United States a “medium-level” pandemic could cause: 89,000 to 207,000 deaths; 314,000 and 734,000 hospitalizations; 18 to 42 million outpatient visits; and another 20 to 47 million people being sick. According to the Centers for Disease Control and Prevention (CDC) (Atlanta, Ga., USA), between 15% and 35% of the U.S. population could be affected by an influenza pandemic, and the economic impact could range between approximately $71 and $167 billion.
Conventional Influenza Vaccination Protocols
The CDC and the leading authorities on disease prevention in the world recommend the single best way of preventing the Flu is through annual Flu vaccination. Conventional vaccines however, typically target the HA and NA antigens, and have been neither universally protective nor 100% effective at preventing the disease.
It is believed that antigenic shift prevents Flu vaccines from being universally protective or from maintaining effectiveness over many years. It is speculated that the ineffectiveness of conventional vaccines may also be due, in part, to antigenic drift and the resulting variation within antigenic portions of the HA and NA proteins most commonly recognized by the immune system (i.e., immunodominant antigens). As a result, many humans may find themselves susceptible to the flu virus without an effective method of treatment available since influenza is constantly improving its resistant to current treatments. This scenario is particularly concerning with respect to the H5N1 virus, which is highly virulent but for which there is currently no widely available commercial vaccine to immunize susceptible human populations.
Currently available flu vaccines must be reformulated and produced each year and generally induce immunity to only a few strains, presumably to those that are currently circulating in humans. In addition, in order to achieve a protective immune response, some vaccines must be administered with high doses of antigen. This is particularly true for H5N1 vaccines. Furthermore, conventional influenza vaccines typically present epitopes in the same order as is found in nature, generally presenting whole viral proteins; consequently, relatively large amounts of protein are required to make an effective vaccine. As a result, each administration includes an increased cost associated with the dose amount, and there is increased difficulty in manufacturing enough doses to vaccinate the general public. Even further, the use of larger proteins elevates the risk of undesirable immune responses in the recipient host.
Antiviral Therapies
Antiviral compounds remain the mainstay for treating inter-pandemic diseases. Currently, they are also the only alternative for controlling pandemics during the initial period when vaccines are not available. Two classes of antiviral compounds are currently on the market: the M2 inhibitors, such as amantadine and rimantadine; and the neuraminidase (NA) inhibitors, which include oseltamivir (Tamiflu®, Roche Laboratories, Inc., Nutley, N.J., USA) and zanamivir (Relenza®, GlaxoSmithKline, Inc., Research Triangle Park, N.C., USA). Both classes of molecules have proven efficacy in prevention and treatment of influenza.
However, limited effectiveness against emergent strains, numerous side effects, and the risk of generating drug-resistant variants remain among the major concerns for limiting their widespread use as chemoprophylactics. In particular, the H1N1 serotype has begun to show significant resistance to oseltamivir, and a recent study by the WHO showed 237 (14%) of 1703 H1N1 viruses had a mutation conferring resistance to the drug. Resistance rates were the highest in Norway (66% of isolates), France (40%), and Luxembourg (25%), and mutation have already been found in 18 of 37 countries where the viruses have been analyzed. The mutation was observed in 8% of the isolates studied in the United States.
Contemporary influenzavirus vaccines and antiviral therapeutics are limited by significant, fundamental shortcomings, and there remains an unmet need in the art for an immunogenic composition that is not as susceptible to changes, due to antigenic shift or drift, for example, which thereby remains effective across various strains and subtypes of influenza from year to year. In particular, new therapeutic and/or prophylactic modalities are needed to address future influenza pandemics, and new vaccines are needed that can complement conventional vaccines to provide more comprehensive protection against the influenza virus than is conventionally available.
It would be highly desirable to have target antigens or epitopes that are conserved across types, subtypes, and/or strains of influenza virus; are easily manufactured and stored so as to improve production capacity and vaccine availability; remain effective through at least two Flu seasons so as to reduce production requirements; require lower concentrations of protein; reduce undesirable immune responses; and enhance protection even when a new human virus emerges or mutations occur in circulating human influenza strains.